One curious aspect of drug addiction is that a majority of people experimenting with illicit drugs do not develop the intense craving and compulsive drug use typifying addiction. Thus, identifying factors rendering a person resistant to addiction has application not only for treatment, but also for prevention of addiction. The current proposal exploits the environmental enrichment paradigm, a non-drug, non-surgical manipulation producing an addiction-resistant phenotype for intravenous drug self-administration in rats. Specifically, rats reared in an enriched condition (EC), group housed in large cages with novel children's toys, self administer less cocaine or amphetamine than rats raised in an isolated condition (IC). Importantly, the decrease in stimulant self administration is specific to self administration and not due to general anhedonia. Our preliminary data offer good evidence that the protective addiction phenotype is due, at least in part, to decreases in activity of the transcription factor cAMP response-element binding protein (CREB), with the net effect of decreasing neuronal excitability of nucleus accumbens (NAc) medium spiny neurons. The purpose of the current proposal is to further investigate neuronal excitability as it relates to addictive behavior and identify specific mechanisms mediating NAc excitability in EC and IC rats. Aim 1 will investigate whether or not decreasing neuronal excitability in the NAc can reduce the propensity for cocaine self administration in IC rats, and also to investigate if decreased excitability will be additive to the protective EC phenotype. Next, Aim 2 will examine mRNA expression of cationic ion channels as possible proximal mechanisms mediating the protective EC phenotype. For example, the study will examine basal expression of excitatory ion channels, hypothesizing decreased expression of specific ion channels in NAc of EC rats relative to IC rats, and for coordinated downregulation of groups of excitatory ion channels. The final aim will confirm mRNA regulation identified by Aim 2 and then study protein expression of these targets in EC, IC and SC rats. The results of these experiments will uncover novel gene targets mediating resistance to addiction. Further, these experiments will identify the critical missing links between CREB activity in the NAc and addiction-relevant behavior. Lastly, these experiments will provide new tools to accelerate understanding of the role of environment in mediating resistance to addiction. PUBLIC HEALTH RELEVANCE: We know that environment plays a critical role in susceptibility to drug addiction, and rearing rats in an enriched environment renders them resistant to addiction-like behavior in models of intravenous self administration. This project will identify molecular mechanisms underlying the protective effect of environmental enrichment and strengthen our understanding of how gene transcription affects behavior. The results of this project will lay the foundation for future treatment and prevention of drug addiction in humans.